Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice

Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H274-83. doi: 10.1152/ajpheart.01031.2006. Epub 2007 Mar 2.


Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia-reperfusion (I/R) injury of the brain, heart, and kidney. However, whether EPO exerts its protection by prevention of postischemic microcirculatory deterioration is unknown. We have investigated the effect of EPO on I/R-induced microcirculatory dysfunctions. We used the mouse dorsal skinfold chamber preparation to study nutritive microcirculation and leukocyte-endothelial cell interaction in striated muscle of the dorsal skinfold by in vivo fluorescence microscopy before 3 h of ischemia and during 5 days of reperfusion. Animals were pretreated with EPO (5,000 U/kg body wt) 1 or 24 h before ischemia. Vehicle-treated I/R-injured animals served as controls. Additional animals underwent sham operation only or were pretreated with EPO but not subjected to I/R. I/R significantly (P < 0.05) reduced functional capillary density, increased microvascular permeability, and enhanced venular leukocyte-endothelial cell interaction during early reperfusion. These findings were associated with pronounced (P < 0.05) arteriolar constriction and diminution of blood flow during late reperfusion. Pretreatment with EPO induced EPO receptor and endothelial nitric oxide synthase expression at 6 h of reperfusion (P < 0.05). In parallel, EPO significantly (P < 0.05) reduced capillary perfusion failure and microvascular hyperpermeability during early reperfusion and arteriolar constriction and flow during late reperfusion. EPO pretreatment substantially (P < 0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. EPO applied 1 h before ischemia induced angiogenic budding and sprouting at 1 and 3 days of reperfusion and formation of new capillary networks at 5 days of reperfusion. Thus our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic inflammation, and inducing new vessel formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Back
  • Blood Flow Velocity / drug effects*
  • Dose-Response Relationship, Drug
  • Erythropoietin / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Microcirculation / drug effects
  • Microcirculation / pathology
  • Microcirculation / physiopathology*
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / physiopathology*
  • Recombinant Proteins
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology*
  • Reperfusion Injury / prevention & control*
  • Skin


  • Recombinant Proteins
  • Erythropoietin